Nanotechnology, the term derived from the Greek word nano, meaning dwarf, applies the principals of both physical and biological sciences at a molecular or submicron level. The materials at nanoscale can be a device or system, or supramolecular structures, complexes or composites. Nanotechnology is making significant advances in biomedical applications, including drug delivery techniques.
The development of drug delivery systems for small molecules, proteins and DNA have been greatly influenced by nanotechnology. Novel drug delivery techniques are an important strategic tool for expanding drug markets. Improved drug delivery systems can address issues associated with currently used drugs such as increasing efficacy or improving safety and patient compliance (Rocco M C and Bainbridge W S, eds Social Implications of Nanoscience and Technology, National Science Foundation Report, 2001). In addition, this technology permits the delivery of drugs that are highly insoluble or unstable in biological environments. It is expected that novel drug delivery systems can make a significant contribution to the pharmaceutical market. Approximately 13% of the current global pharmaceutical market is sales of products incorporating a drug delivery system. The demand for drug delivery systems in the United States alone is expected to grow nearly 9% annually to more that US$82 billion (Rocco M C and Bainbridge W S, eds, Converging Technologies for Improving Human Performance, National Science Foundation and Department of Commerce Report, Kluwer Academic Publishers, 2002).
Many therapeutic agents have not been successful because of their limited ability to reach the target tissue. In addition, new delivery systems for anti-cancer agents, hormones, proteins, peptides and vaccines are necessary because of safety and efficacy problems with conventional administration modalities. For example, cytotoxic cancer drugs can damage both malignant and normal cells. A drug delivery system that targets the drug to the malignant tumor would decrease bystander toxicity. Protein and DNA drugs must be administered intravenously due to their instability at the high pH in the stomach after oral administration. Additional problems include premature loss of efficacy due to rapid clearance and metabolism. Drug delivery systems that can deliver protein, nucleic acid or unstable small molecules are highly desirable and are currently the subject of ongoing, and as yet unsuccessful, research.
There has been considerable research into developing biodegradable nanoparticles as effective drug delivery systems (Panyam J et al., Biodegradable nanoparticles for drug and gene delivery to cells and tissue, Adv Drug Deliv Rev. 55:329-47, 2003). Nanoparticles are solid, colloidal particles consisting of macromolecular substances that vary in size from 10-1000 nanometers. The drug of interest is either dissolved, entrapped, adsorbed, attached or encapsulated into the nanoparticle matrix. The nanoparticle matrix can be comprised of biodegradable materials such as polymers or proteins. Depending on the method of preparation, nanoparticles can be obtained with different properties and release characteristics for the encapsulated therapeutic agents (Sahoo S K and Labhasetwar V, Nanotech approaches to drug delivery and imaging, DDT 8:1112-1120, 2003).
The advantages of using nanoparticles for drug delivery result from their two main properties. First, nanoparticles, because of their small size, can penetrate through smaller capillaries and are taken up by cells, which allows efficient drug accumulation at the target sites (Panyam J et al., Fluorescence and electron microscopy probes for cellular and tissue uptake of poly (D,L-lactide-co-glycolide) nanoparticles, Int J Pharm. 262:1-11, 2003). Second, the use of biodegradable materials for nanoparticle preparation allows sustained drug release within the target site over a period of days or even weeks. Nanoparticles can also be effective drug delivery mechanisms for drugs whose targets are cytoplasmic.
Targeted delivery of nanoparticles can be achieved by either passive or active targeting. Active targeting of a therapeutic agent is achieved by conjugating the therapeutic agent or the carrier system to a tissue or cell-specific ligand (Lamprecht et al., Biodegradable nanoparticles for targeted drug delivery in treatment of inflammatory bowel disease, J Pharmacol Exp Ther. 299:775-81, 2002). Passive targeting is achieved by coupling the therapeutic agent to a macromolecule that passively reaches the target organ (Monsky W L et al., Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor, Cancer Res. 59:4129-35, 1999). Drugs encapsulated in nanoparticles or drugs coupled to macromolecules such as high molecular weight polymers passively target tumor tissue through the enhanced permeation and retention effect (Maeda H, The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting, Adv Enzyme Regul. 41:189-207, 2001; Sahoo SK et al., Pegylated zinc protoporphyrin: a water-soluble heme oxygenase inhibitor with tumor-targeting capacity, Bioconjugate Chem. 13:1031-8, 2002).
As macromolecules such as proteins and nucleic acids play a larger role in the therapy of disease and traditional pharmaceutical small molecules are abandoned during development due to their inability to effectively reach their intended target, improved drug delivery systems are needed. The delivery of a wide variety of drugs is hindered because they have difficulty crossing the blood brain barrier. A characteristic function of nanoparticles is their ability to deliver drugs across biological barriers to the target site and to protect the drugs from the biological environment until they reach the target site. Therefore, the use of nanoparticle delivery systems is a promising way to improve the delivery of a wide variety of bioactive agents.